An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency (OTC-HOPE)

• ClinicalTrials.gov Identifier: NCT06255782
• Recruitment Status: Recruiting
• First Posted: February 13, 2024
• Last Update Posted: April 10, 2024
• Sponsor: iECURE, Inc.
• Information provided by (Responsible Party): iECURE, Inc.

Study Description

Brief Summary:

Ornithine Transcarbamylase (OTC) deficiency, the most common urea cycle disorder, is an inherited metabolic disorder caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build-up excess levels of ammonia in their blood, potentially resulting in devastating consequences, including cumulative and irreversible neurological damage, coma and death. The severe form of the condition emerges shortly after birth and is more common in boys than girls.

This is a Phase 1/2, open-label, multicenter, safety and dose finding study of ECUR-506 in male babies with neonatal onset OTC deficiency. The primary objective of this study is to evaluate the safety and tolerability of up to two dose levels of ECUR-506 following intravenous (IV) administration of a single dose.

Condition or disease	Intervention/treatment	Phase
Ornithine Transcarbamylase Deficiency; Ornithine Transcarbamylase Deficiency Disease; Ornithine Carbamoyltransferase Deficiency (Disorder); Urea Cycle Disorders, Inborn	Genetic: ECUR-506	Phase 1; Phase 2

Detailed Description:

The study drug, ECUR-506, is an investigational gene editing therapy. Gene editing is a way to repair, replace, or introduce new copies of genes that don't work. The study drug contains a working copy of the OTC gene that will be delivered by an IV infusion. It also contains a gene to encode the editing enzyme which is the part of the study drug that can cut DNA so that the OTC gene can be inserted. The study drug was designed to introduce a working copy of the OTC gene and a gene to encode the editing enzyme. A gene cannot enter cells by itself, it needs a delivery mechanism to move the gene into the cells. In this study, the carrier is called adeno-associated virus (AAVs) that is able to enter cells and deliver these genes. This is a commonly found virus that has been changed to make it essentially harmless.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose escalation with dose staggering in Cohort 1 and 2. Dose selection for the Expansion Cohort will be based on an assessment of the totality of the safety and efficacy.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Efficacy of a Single Intravenous (IV) Administration of ECUR-506 in Males Less Than 9 Months of Age With Genetically Confirmed Neonatal Onset Ornithine Transcarbamylase (OTC) Deficiency
• Estimated Study Start Date: April 2024
• Estimated Primary Completion Date: September 2026
• Estimated Study Completion Date: September 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; Participants will receive the Low Dose of ECUR-506 delivered one time via IV Infusion.	Genetic: ECUR-506; ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.
Experimental: Cohort 2; Participants will receive the High Dose of ECUR-506 delivered one time via IV infusion.	Genetic: ECUR-506; ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.
Experimental: Expansion Cohort; Participants will receive ECUR-506 at one of the doses evaluated in Cohort 1 or Cohort 2 one time via IV infusion.	Genetic: ECUR-506; ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.

Outcome Measures

Primary Outcome Measures :

1. Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness) [ Time Frame: Over 24 weeks post infusion ]

   Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, electrocardiograms, and any other medically indicated assessments from the time informed consent is signed through the end of the safety follow-up period.

   AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity following the administration of the study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.

2. Urinalysis evaluations [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]

   Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, electrocardiograms, and any other medically indicated assessments from the time informed consent is signed through the end of the safety follow-up period.

   AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity following the administration of the study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.

Secondary Outcome Measures :

1. Percent liver transduction [ Time Frame: Assessed at Week 24 ]
   Pharmacokinetics
2. Number of hyperammonemic crises (HAC) [ Time Frame: Over 24 weeks post infusion ]
   Pharmacodynamics and Efficacy
3. qPCR measurement to evaluate the clearance of both vectors in blood over time [ Time Frame: Over 24 weeks post infusion ]
   Pharmacokinetics
4. qPCR measurement to evaluate the clearance of both vectors in urine over time [ Time Frame: Over 24 weeks post infusion ]
   Pharmacokinetics
5. qPCR measurement to evaluate the clearance of both vectors in feces over time [ Time Frame: Over 24 weeks post infusion ]
   Pharmacokinetics
6. Scavenger drug dose per body surface area (BSA) [ Time Frame: Over 24 weeks post infusion ]
   Efficacy
7. Protein allowance g/kg [ Time Frame: Over 24 weeks post infusion ]
   Efficacy
8. Blood urea nitrogen measurements [ Time Frame: Over 24 weeks post infusion ]
   Pharmacodynamics

Other Outcome Measures:

1. Number of participants with antibodies to hOTC in blood [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Pharmacodynamics
2. Number of participants with antibodies to M2PCSK9 in blood [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Pharmacodynamics
3. Number of participants with antibodies to AAVrh79 in blood [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Pharmacodynamics
4. Daily ammonia levels during hospitalization requiring ICU care for HAC event [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Pharmacodynamics and Safety
5. Time to liver transplant from dosing to end of study (EOS) [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Efficacy
6. Number of instances the participant is eligible for medical management adjustments based on iECURE guidance (protein diet or scavenger medication) [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Efficacy
7. Plasma ammonia and plasma glutamine levels [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Pharmacodynamics
8. Serum PCSK9 [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Pharmacodynamics
9. Change from baseline at Week 24 post infusion in Bayley Scales of Infant and Toddler Development 4th Ed (BSID-4) for the Cognitive, Language, and Motor scales [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
   Total Raw Scores, Growth Score Values (GSVs), and Age Equivalent Scores will be analyzed; Raw Scores range 0-162; GSVs range 428-599; Age Equivalent Scores range 1-42 months; a higher score reflects a higher level of skill.
10. Quality of Life, as measured by the Pediatric QOL inventory Infant Scale (PedsQL-IS) [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
    Quality of Life
11. Urinary excretion of phenylacetate metabolites [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
    Urinary phenylacetate (mcg/mL), urinary phenylacetylglutamine (mcg/mL), urinary phenylacetate/ phenylglutamine ratio.
12. Urinary excretion of orotic acid metabolites. [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
    Urinary orotic acid (mmol/ mol creatinine), urinary uracil (mmol/mol creatinine).
13. Change from baseline at Week 24 post infusion in length. [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
    Length measured in centimeters.
14. Change from baseline at Week 24 post infusion in weight. [ Time Frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. ]
    Weight measured in kilograms.
15. Assess the potential on target editing by amplicon-seq in liver tissue samples of participants who received ECUR-506. [ Time Frame: The following will be assessed at week 24 if liver biopsy tissue sample is sufficient. ]
    Pharmacodynamics
16. Assess potential off-target editing with AAV vector ITR insertion by ITR-seq in liver tissue samples of participants who recieved ECUR-506 [ Time Frame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient. ]
    Pharmacodynamics
17. Assess for potential genetic changes in the liver tissue, collected by liver biopsy, through long read sequencing, in participants who have received ECUR-506 [ Time Frame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient. ]
    Pharmacodynamics
18. With an observed genetic safety signal, genetic analysis of Whole Blood DNA may be performed on samples collected and stored at screening and week 24, in the event of an observed genomic safety signal. [ Time Frame: Assessed as any difference between screening and week 24 genetic markers, if a genetic safety signal is observed. ]
    Safety

Eligibility Criteria

• Ages Eligible for Study: 24 Hours to 7 Months (Child)
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Males present with the highest unmet medical need, and in order to reduce the variability of the study population, participants are restricted to the male sex . OTC is primarily inherited in an X-linked recessive pattern, meaning that it mostly affects males, who only have one copy of the X chromosome. Females, who have two X chromosomes, can be carriers of the condition. Some females may experience milder OTC symptoms, or they may have no symptoms.
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male sex
2. Gestational age ≥ 37 weeks
3. Age at screening is 24 hours to 7 months*

4. Genetically confirmed OTCD

   • Documented analysis either through prenatal testing or post-birth genetic testing.

   Note: a prenatal testing diagnosis will be confirmed post-birth and prior to dosing.

5. Severe neonatal OTCD defined by the following:

   • Current or past hyperammonemic crisis (which includes but is not limited to: severely elevated [>8 x ULN] ammonia levels, lethargy, poor feeding, coma, seizure) within first week of life OR
   • Family history and genetic confirmation of pathogenic or likely pathogenic variant consistent with severe OTC, or has same genetic mutation as previous family member who had severe disease with neonatal onset within first week of life AND
   • Currently receiving treatment (e.g., dietary and scavenger therapy)
6. In participants not prenatally diagnosed, current or historical (within 2 weeks prior to Screening) biochemical profile consistent with OTC: below LLN of plasma citrulline/arginine and urine orotic aciduria at time of diagnosis
7. Participant's parent(s)/LAR must be able to comprehend and be willing to provide a signed IRB/IEC-approved ICF which will include consent for participation in this 24-week trial with immediate roll-over into the 14.5 year ECUR-LTFU study *Participant's age at screening: Any subsequently enrolled participant must be stabilized and dosed by less than 9 months of age. Participants ≥5 months and ≤ 7 months at screening will therefore have a shortened stabilization window (i.e., <120 days) to achieve dosing prior to turning 9 months of age. No exceptions to dosing age will be granted.

Exclusion Criteria:

1. Neonatal diagnosis of severe to profound Hypoxic Ischemic Encephalopathy (based on standard HIE metrics) due to birth injury
2. Requiring urgent liver transplant due to liver failure as assessed by the PI.
3. Contiguous gene deletion involving the OTC gene
4. Known or suspected major organ injury/dysfunction/anomalies (brain, heart, liver, kidneys) other than what is consistent with OTCD, based on routine medical assessments performed as part of standard of care.
5. Treatment with any other gene therapy or gene editing therapy
6. Co-enrollment in any other clinical study with an investigational product prior to or during the duration of this trial would require the participant to be withdrawn from this study
7. Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data
8. Documented vertical transmission of HSV, HIV, or HepA/HepB/HepC
9. Documented in-utero teratogen, substance, and/or alcohol exposure, which in the opinion of the Investigator may increase the participant's risk of developmental delays, congenital anomalies, and/or significant medical complications

Contacts and Locations

Contacts

Contact: George Diaz, M.D., Ph.D.; 1-877-694-3558; medinfo@iecure.com

Contact: Trial Recruitment; clinicaltrials@iecure.com

Locations

United Kingdom

Great Ormond Street Hospital; Recruiting

London, United Kingdom

Contact: Christopher Jackson christopher.jackson@gosh.nhs.uk

Sponsors and Collaborators

iECURE, Inc.

Investigators

• Study Director: George Diaz, M.D., Ph.D; iECURE, Inc.

More Information

• Responsible Party: iECURE, Inc.
• ClinicalTrials.gov Identifier: NCT06255782
• Other Study ID Numbers: ECUR-506-OTC-101; OTC HOPE ( Other Identifier: iECURE, Inc. )
• First Posted: February 13, 2024
• Last Update Posted: April 10, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by iECURE, Inc.:

Amino Acid Metabolism, Inborn Errors; Ammonia; Brain Diseases; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Central Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; High Ammonia; Hyperammonemia; Inborn; Inborn Errors; Liver Disease; Liver Transplant; Metabolism; Metabolic Diseases; Metabolism, Inborn Errors; Neonatal; Nervous System Diseases; NH4; Ornithine; Ornithine Transcarbamylase Deficiency; OTC; OTC Deficiency; OTCD; Transcarbamylase; UCD; Urea Cycle Disorders; X-Linked

Additional relevant MeSH terms:

Urea Cycle Disorders, Inborn; Ornithine Carbamoyltransferase Deficiency Disease; Deficiency Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Malnutrition; Nutrition Disorders; Genetic Diseases, X-Linked